THE MITOCHONDRIAL GENETICS MAZE .

The inheritance patterns of the mitochondrial encephalomyopathies can be quite complicated. The mutations that cause these diseases can be in the chromosomes; this is what's usually meant when people talk about a genetic or inherited disease.

But mitochondrial encephalomyopathies have a unique situation. People can also inherit one of these diseases through mutations in the mitochondrial DNA (mtDNA), which comes from the mother only. Mitochondria are the only parts of the cells that have their own DNA, separate from that of the chromosomes in the cell's nucleus, called nuclear DNA.

This situation occurs because the mitochondrial respiratory chain, which is the final step in the energy-making process, is made up of proteins that come from both nuclear and mtDNA (see illustration). Although only 13 of roughly 100 respiratory chain proteins come from the mtDNA, these 13 proteins contribute to every part of the respiratory chain except complex II, and 24 other mitochondrial genes are required just to manufacture those 13 proteins. Thus, a defect in either a nuclear gene or one of the 37 mitochondrial genes can cause the respiratory chain to break down. (This respiratory chain has nothing to do with breathing.)

When mitochondrial disease is caused by defects in the nuclear DNA, the inheritance follows a "Mendelian" pattern, just as other inherited disorders do (named for Gregor Mendel, the 19th-century scientist who first explained inheritance). These inheritance patterns include autosomal dominant, autosomal recessive and X-linked. Leigh syndrome (caused by defects in complexes I and IV) is one of the most common forms of mitochondrial encephalomyopathy inherited in this fashion. It's usually autosomal recessive, meaning that two copies of the defective gene, one from each parent, are required to produce the disease.

Although nuclear DNA defects are relatively straightforward, when a disease is caused by defects in the mtDNA, it gets more complex. Mitochondrial genetics are made thornier by the fact that, instead of inheriting two copies of each mitochondrial gene (one from the father and one from the mother) in the way that nuclear genes are inherited, you inherit from your mother literally hundreds of thousands of copies of the 37 mitochondrial genes, while you inherit no mtDNA from your father. (Each of the roughly 100,000 mitochondria in the mother's egg cell may contain between two and 10 copies of the mtDNA genes.)

Also, when a mutation occurs in the mtDNA, only some of the many copies of mtDNA distributed within the mitochondria of each cell will carry the mutation -- a situation known as heteroplasmy (see illustration below). The ratio of mutant to normal mtDNA in each tissue, along with other factors, may determine the severity of the disease in an individual.

"And therefore the nice rules that Mendel introduced over a century ago to explain autosomal recessive, dominant and X-linked inheritance do not apply," says Salvatore DiMauro, an MDA researcher at Columbia University in New York, who has studied mitochondrial disorders for over 30 years.

The only "rules" for inheritance of mtDNA mutations that can be counted on are that a father can't pass on mtDNA mutations and a mother will pass on mtDNA mutations to 100 percent of her offspring. This pattern is known as maternal inheritance.

But, even though all of a woman's children will inherit her mtDNA mutations, that doesn't make it easy to predict how severe the disease will be in each child. This is because the ratio of mutant to normal mtDNA passed from mother to child can vary dramatically and unpredictably with each pregnancy. Thus a mother with very mild symptoms of mitochondrial disease, perhaps not even diagnosed as such, may give birth to one child with a very severe disease and a second child with no disease symptoms at all. Some researchers believe this is caused by a "bottleneck" effect during the maturation of the mother's egg cells (see chart below).

Some mitochondrial encephalomyopathies that may be caused by mtDNA mutations and are subject to the rules of maternal inheritance are MERFF, MELAS, NARP, PEO and MILS.

In some syndromes, mtDNA mutations tend to occur spontaneously -- that is, the mutation isn't present in the mother or the father but has, instead, occurred very early in the development of the embryo. This is often the case for KSS, PEO and Pearson, three diseases that result from a type of mtDNA mutation called a deletion (specific portions of the DNA are missing) or mtDNA depletion (a general shortage of mtDNA). These types of spontaneously acquired mutations aren't usually passed to the next generation.

A third kind of mitochondrial disease inheritance is a combination of nuclear and mtDNA defects. This type of disease is inherited in a Mendelian fashion, indicating the involvement of a nuclear gene, but is also characterized by mtDNA deletions. In this case, the mtDNA deletions occur because there's a "breakdown in communication" between the nuclear and mitochondrial DNA.

An example of this type of disease is MNGIE. Recently, Columbia University researcher Michio Hirano and colleagues identified the nuclear gene involved in MNGIE. The gene codes for a protein called thymidine phosphorylase that may be involved in regulating the building blocks of mitochondrial DNA.

When mitochondrial disease is caused by nuclear DNA mutations, the symptoms and their severity are very consistent within families. But symptoms can vary widely even within the same family if the disease is caused by an mtDNA mutation.

No one knows this better than the Haas family of Charlotte, N.C. Jonathan, 11; Timothy, 9; and their mother, Sandra, all have a mitochondrial encephalomyopathy with maternal inheritance.

The Downs Family

Sandra Haas never knew that she had a mitochondrial disorder until the disease was diagnosed in her first biological son, Jonathan. Now she can make sense of symptoms she only vaguely understood before.

"It's hard to explain," she says, "but I have a hard time if I walk a distance, like if I'm trying to go through the airport. If I push myself, I just have to totally stop or my legs are just going to go out from under me."

In contrast, Jonathan has more severe muscle weakness in his legs. He uses a wheelchair to travel more than a short distance, and he gets muscle cramps at night when he has overexerted himself during the day.

In Timothy, on the other hand, the disease seems to have affected his brain more than his muscles.

"Timothy is very bright and personable," says Haas. "He's never met a stranger. And he can hear a song and sing it, or he can watch something on TV and tell you exactly what was said. But in school he just can't get the simple things like the ABCs."

Heteroplasmy -- the variation of mutations among copies of mtDNA within a cell -- may account for the very different symptoms in members of the same family.

DiMauro explains that when you have a mutation in mtDNA, all cells in the body will contain the mutated DNA, and, in theory, all tissues should be affected.

"But," says DiMauro, "the trick is in the percentage of mutant mitochondria in each tissue. Because different tissues have different energy needs, the percentage of the mutation needed to cause problems varies." This phenomenon is called the threshold effect.

"For example, if 70 percent of the mtDNA in the liver is mutated, that liver may still function pretty well without causing any symptoms. But the same percent in brain, or in muscle, may cause problems," he says. Thus, brain and muscle can be said to have a low threshold for tolerating mitochondrial mutations.

The idea of an energy threshold explains the variability in clinical presentation of people with mitochondrial diseases, even in the same family. It also explains why these diseases are multisystemic syndromes, DiMauro says.

In other words, even though the two Haas boys got exactly the same mtDNA mutation from their mother, they may have gotten different doses of normal vs. mutant mtDNA, and the mutant DNA may have distributed itself differently in their tissues.

DiMauro says that many doctors once discounted the idea that mutations in the mtDNA could cause disease. Then, in 1988, it was discovered that mutations in mtDNA can lead to disease and a torrential amount of research opened up. Recently, interest in mitochondria has redoubled as scientists find that mitochondrial dysfunction may be involved in phenomena as diverse as diabetes, amyotrophic lateral sclerosis (ALS) and aging.

There's no doubt that the resurgence of interest will yield new information about mitochondrial disorders and their management.